Matrix Contains Sequestered Signalling Molecules
While the major dentine inorganic component is hydroxyapatite, its organic matrix is mainly composed of collagen I and non-collagenous proteins such as dentine sialoprotein [18] and dentine matrix protein-1 [19]. These are involved in the initiation and the regulation of dentine mineralisation. In addition, different signalling molecules have been reported to be secreted by the odontoblasts and sequestered in the dentine matrix, mainly in an inactive form. Among others, these include transforming growth factor-β1 (TGF-β1), basic fibroblast growth factor (FGF-2), vascular endothelial growth factor (VEGF), and platelet derived growth factor (PDGF) [20, 21]. During the carious dissolution of the dentine matrix, these molecules can be released and reach the underlying odontoblasts leading to the upregulation of their synthetic activity.
In addition to the responsiveness to these growth factors, recent data demonstrated that odontoblasts act as sensor cells as they express transient potential channel receptors. These receptors allow the odontoblast to be responsive to the external stimulations, such as noxious heat, noxious cold, as well as chemical and mechanical stimulations [22]. Thus, upon stimulation, odontoblasts synthesise a new tertiary dentine at the pulp periphery facing the stimulation site. This focally secreted dentine can also be deposited within the dentine tubules to decrease their permeability to cariogenic bacteria and their toxins, leading to the protection of the underlying pulp.
Thus, odontoblasts represent the first defence mechanism in case of carious lesion development. Indeed, these cells also express receptors called Toll-like receptors (TLRs) 2 and 4 [23, 24], which recognise specific structures on Gram-positive and Gram-negative bacteria, respectively. These TLRs belong to a big family of pattern recognition receptors that are activated after contact with common molecules on the pathogen surface. In moderate carious injuries, TLRs 2 are highly expressed in the underlying odontoblasts [25]. Upon activation, these TLRs induce the secretion of antimicrobial molecules such as β-defensins and nitric oxide by the odontoblasts which have an antibacterial effect against S. mutans, thus limiting cariogenic bacteria progression towards the pulp [26]. Also, upon activation of their receptors, odontoblasts secrete proinflammatory chemokines which lead to dendritic cell recruitment in order to eliminate the pathogenic agents [27].
Overall, in the case of moderate dentine carious lesions, the odontoblasts act as a barrier exerting antimicrobial effects and initiating the secretion of a tertiary dentine to protect the underlying pulp (Fig. 3).
However, in the case of severe and rapidly progressive carious lesions, tertiary dentine focal synthesis may not be enough and bacteria may destroy the newly synthesised tertiary dentine, reach the underlying pulp, and induce an inflammatory reaction (Fig. 4).
The Dental Pulp Defence Strategies
When the odontoblastic barrier is destroyed by the carious lesion and either bacteria or their toxins reach the underlying pulp, a tertiary dentine secretion can still be observed. This dentine, which is secreted after the odontoblast destruction, is synthesised by another cell type originating for the differentiation of adult pulp stem cells. This reparative dentine usually contains fewer tubules than the physiological one. This might decrease the bacterial infiltration or their toxins to the underlying pulp. While little was known about the cells secreting this dentine, the discovery of adult stem cells within the dental pulp provided a significant step forward. Indeed, all dental pulps in permanent and primary teeth and at all ages comprise, at least, a population of adult stem cells [28]. This was first demonstrated in a culture system of cells isolated from the pulps of third molars, where pulp cells were able to produce a mineral matrix with molecular and mineral characteristics of dentine [29]. Additionally, when isolated with specific mesenchymal stem cell markers such as STRO-1 and transplanted after mixing with hydroxyapatite/tricalcium phosphate ceramic powder subcutaneously in mice, they generated a dentine/pulp-like tissue [30]. There is converging evidence that one of the niches of these stem cells is located in the perivascular area. After pulp injury, these cells are activated and migrate to the injury site to synthesise the tertiary dentine [31]. It has been reported that TGF-β1, which can be released after the dissolution of dentine, is involved in the recruitment of these cells and their differentiation into odontoblast-like cells secreting the tertiary dentine [32].
Fig. 3. a Histology of a moderate carious lesion in a molar. It is characterised by a disorganised dentine with a loss of the typical tubular structure at the carious site. b Tertiary dentine is secreted locally by the underlying odontoblasts (od). At this stage, bacterial infiltration is arrested at a distance from the pulp, which has a normal aspect.
Additionally, recent investigations on dental pulp, which has a terminal circulation, revealed that, in addition to the systemic regulation, it has a local regulation of its vascularisation, inflammation, and regeneration. This allows the dental pulp to resist bacterial invasion by different mechanisms, as explained below.
Dental Pulp Local Regulation
It is well established that carious injury leads to pulp hypoxia. Different pulp cell types, such as fibroblasts, endothelial, and stem cells, have been reported to upregulate the synthesis of hypoxia-inducible factor, which increases the synthesis of angiogenic growth factors such as VEGF, FGF-2, and PDGF. This leads to vasodilation and the increased formation of blood vessels at the carious injury site. Overall, this increases nutrient, blood, and oxygen supply to the injured tissue. This also allows inflammatory cell recruitment to carry out phagocytosis of pathogens. After complete pulp healing, there is a downregulation of angiogenic factor secretion and a return to normoxia with normal pulp vascularisation [33].
Fig. 4. a Histology of a severe carious lesion in a molar. It is characterised by a disorganised dentine at the carious site. b Tertiary dentine is produced in the form of a bridge by the underlying odontoblasts. At this stage, bacteria infiltrated the dentine tubules (c) and the pulp, which appears inflamed and infiltrated by numerous inflammatory cells (d).
Carious injury also leads to a pulp inflammatory reaction initiated by complement activation. Complement is the name given to about 40 proteins synthesised mainly by the liver and released in the plasma. During the inflammatory process, the complement is activated, leading to the synthesis of biologically active complement fragments. These play a major role
